The leading cause of death in the USA, heart failure most often represents slow progression of multi-factorial disease, diagnosed as "idiopathic" dilated cardiomyopathy. While the prognosis of treated heart failure continues to be poorer than for most malignancies, there is substantial patient variability in incidence and clinical course that implies the existence of unknown modifiers. We hypothesize that inter-individual differences in susceptibility to and progression of heart failure result from poorly defined environmental and genetic stressors. We have previously defined variations (polymorphisms or mutations) in critical cardiac genes that, alone or in combination, modify or cause heart failure. As some of these variants cluster in distinct ethnic groups, they may constitute a mechanism for known differences in prevalence and outcome of heart failure among ethnic minorities. The five Projects of this SCCOR will examine naturally-occurring genetic or transcriptional events within cardiac adrenergic signaling pathways. Project 1 (Liggett) will extend his highly successful survey of and a2-adrenergic receptor polymorphisms in heart failure, focusing on combinatorial effects of different receptor haplotypes on myocardial contractility. Related Project 2 (Dorn) will examine the roles of novel variants of alpha-1-adrenergic receptors and cardiac-expressed RGS and GRK proteins on cardiac hypertrophy and its progression to heart failure. Project 3 (Kranias) follows up her recent description of a phospholamban mutant that causes lethal familial cardiomyopathy with clinical and basic investigations of newly discovered polymorphisms for phospholamban and phosphatase inhibitor 1 (PPI1) as genetic risk factors for heart failure. Related Project 4 (Molkentin) will define the interactions of PPI1 with protein kinase Cot, itself transcriptionally upregulated in heart failure, and delineate their combined effects on myocardial responsiveness to adrenergic agonists. Project 5 (Robbins) will use transgenesis in human-like rabbit hearts to establish the effects of altered alpha/beta-myosin heavy chain expression on cardiac responses to environmental stressors. Studies will be performed in human subjects, genetically modified animal models, and cultured cells, and are supported by Cores for Genomics, Biostatistics, Stem Cell Manipulation, and Clinical Research Skills Development. We believe this thematically linked, multidisciplinary Center will continue to break new ground in understanding the pathogenesis and optimal management of heart failure.